The implantation of medical devices has become a relatively common technique for treating a variety of medical or disease conditions within a patient's body. Depending upon the conditions being treated, today's medical implants can be positioned within specific portions of a patient's body where they can provide beneficial functions for periods of time ranging from days to years. A wide variety of medical devices can be considered implants for purposes of the present invention. Such medical devices can include structural implants such as stents and internal scaffolding for vascular use, replacement parts such as vascular grafts, or in-dwelling devices such as probes, catheters and microparticles for monitoring, measuring and modifying biological activities within a patient's cardiovascular system. Other types of medical implants for treating different types of medical or disease conditions can include in-dwelling access devices or ports, valves, plates, barriers, supports, shunts, discs, and joints, to name a few.
For example, cardiovascular disease, commonly referred to as atherosclerosis, remains a leading cause of death in developed countries. Atherosclerosis is a disease that results in the narrowing, or stenosis, of blood vessels which can lead to heart attack or stroke if the narrowing progresses to the point of blocking blood flow through the narrowed blood vessels forming the coronary arteries. Cardiovascular disease caused by stenotic or narrowed coronary arteries is commonly treated using either a coronary artery by-pass graft (CABG) around the blockage, or a procedure called angioplasty where a balloon catheter is inserted into the blocked coronary artery and advanced until the vascular stenosis is reached by the advancing balloon. The balloon is then inflated to deform the stenosis open, restoring blood flow.
However, angioplasty or balloon catheterization can result in internal vascular injury which may ultimately lead to reformation of narrowing vascular deposits within the previously opened artery. This biological process whereby a previously opened artery becomes re-occluded is referred to as restenosis. One angioplasty variation designed to reduce the possibility of restenosis includes the subsequent step of arterial stent deployment within the stenotic blockage opened by the expanded balloon. After arterial patency has been restored by expanding the angioplasty balloon to deform the stenotic lesion open, the balloon is deflated and a vascular stent is inserted into the tubular bore or vessel lumen across the stenosis site. The catheter is then removed from the coronary artery lumen and the deployed stent remains implanted across the opened stenosis to prevent the newly opened artery from constricting spontaneously or narrowing in response to the internal vascular injury resulting from the angioplasty procedure itself. However, it has been found that in some cases of angioplasty and angioplasty followed by stent deployment that restenosis may still occur.
Treating restenosis generally requires additional, more invasive, procedures including CABG in some cases. Consequently, methods for preventing restenosis, or for treating incipient forms of restenosis, are being aggressively pursued. One promising method for preventing restenosis is the administration of medicaments that block the local invasion or activation of monocytes, white blood cells that respond to injury or infection, thus preventing the associated secretion of growth factors within the blood vessel at the restenosis site that can trigger vascular smooth muscle cell (VSMC) proliferation and migration causing thickening of the vessel wall and subsequent narrowing of the artery. Metabolic inhibitors such as anti-neoplastic agents are currently being investigated as potential anti-restenotic compounds for such purposes. However, the toxicity associated with the systemic administration of known metabolic inhibitors has more recently stimulated development of in situ or site-specific drug delivery designed to place the anti-restenotic compounds directly at the target site within the potential restenotic lesion rather than generally administering much larger, potentially toxic doses to the patient.
For example, one particular site-specific drug delivery technique known in the art employs the use of vascular stents coated with anti-restenotic drugs. These stents have been particularly useful because they not only provide the mechanical structure to maintain the patency or openness of the damaged vessel, but they also release the anti-restenotic agents directly into the surrounding tissue. This site specific delivery allows clinically effective drug concentrations to be achieved locally at the stenotic site without subjecting the patient to the side effects that may be associated with systemic drug delivery of such pharmaceutical compounds. Moreover, localized or site specific delivery of anti-restenotic drugs eliminates the need for more complex specific cell targeting technologies intended to accomplish similar purposes.
An important factor in the efficacy of in situ drug delivery is how the drug is attached to the stent and delivered to the target site as a result. More specifically, a sufficient amount of deliverable drug needs to be releasably attached to and associated with the stent or implantable drug delivery vehicle. Typically, as known in the art, anti-restenotic drugs are releasably attached to the surfaces of implantable drug delivery devices such as stents through chemical bonding with the surface through either non-covalent or covalent bonding. Non-covalent bonds are generally weaker than covalent chemical bonds and therefore release the bound drugs more easily. Conversely, covalent chemical bonds are generally stronger and hold on to the bound drugs more securely, providing easier handling and storage.
An alternative approach to binding pharmaceutical compounds to the surfaces of implantable medical devices utilizes coatings rather than binding the drugs directly to the surfaces of the implants. For example, drugs can be incorporated into or applied to a polymer layer that is itself applied to the surface of the implant. A variety of polymers have been developed in the art which are intended to allow for drug attachment to medical implants and for subsequent delivery. Such materials are disclosed in U.S. Pat. Nos. 6,278,018, 6,214,901, and 5,858,653, incorporated herein by reference.
As noted above, an important factor in the efficacy and the utility of such in situ drug delivery techniques and devices is the ability to release an effective dose of the drug at the appropriate time for the appropriate duration. In most prior art technologies the drug delivering implants are coated with a polymer that binds or holds the drug within the polymer coating and releases the drug as the polymer coating is broken down by normal processes within the patient's body or the drug simply diffuses out of the polymer coating once it is in an aqueous or wet environment. Typically, these drug release mechanisms result in what is known as dumping or the relatively sudden release of the majority of the bound drugs over a relatively short period of time.
Additionally, this sudden release profile results in the amount of drug being delivered to the target site rapidly tapering off over time. As a result, an effective drug dose is delivered only for a short period of time following implantation. This can result in a less than effective administration of the drug. Thus, while these prior art drug releasing coating technologies have been useful and promising, a strong need exists for a site specific drug delivery technology utilizing medical implants where the drug release profiles and the associated drug dosages can be controlled over time. It is an object of the present invention to address this and other needs.